Substituted imidazoles



Patented Apr. so, 1946 T 2,399,601

UNITED STATES PATENT oEFicE SUBSTITUTED IMIDAZOLES Lucas P. Kyrides,Webster Groves, and Ferdinand B. Zlenty, St. Louis, Mo., assiznors toMonsanto Chemical Company, St. Louis, Mo., a corporation of Delaware NoDrawing. Application April 15, 1943,

Serial No. 483,172

4 Claims. (Cl. 260--309.6)

The present invention relates to the production diately thereafter andbefore the products are of new therapeutic agents and insecticidetoxiisolated from the reaction mixture. cants which are substitutedimidazole compounds The products of the present invention have also andcomprises the method of producing these been found to possess utility-as insecticides and compounds as well as the new products them- 5 astoxicants for insecticide compositions, such as selves. sprays andpowders, in which the compounds are According to the present inventiongenerally blended with suitable wetting agents, fillers, solstated, newproducts which are valuble in the .vents, adhesives, coating agents,repellents and.

treatment of various diseases are made by preother ingredients employedin compounding inparing 2-alkyl and 2-allrenyl imidazoles havingsecticides.

the formula: a The products of the present invention may be prepared byreacting ethylene diamine with a H l1)R molecular equivalent of anacylating agent comprising an aliphatic monocarboxylic acid having N 16as its alkyl or alkenyl residue one of the residues in which Rrepresents an acyclic hydrocarbon described hereinbefore in thedefinition of R with radical having from 13 to 14 carbon atoms in itsrespect to the e e acid t s e p y structure. The acyclic hydrocarbonradical may will be composed of an alkyl or alkenyl residue be composedof a single straight chain such as f the p per chain length or with thepr the n-tridecyl and n-tetradecyl radicals or the he ai co nents, to etr with a c runsaturated n-trldecenyl and n-tetradecenyl radli cid p, hear on of which is no icals. Likewise, the acyclic hydrocarbo radicalincluded in the contemplation of the chain length may b a, bran h d haiisomer of these radicals hereinbefore described, In place of the acid,the havin a structure in which at least 10 carbon aikyl es e such as thebutyi ester, or desirably atoms are in one chain. The remainder of thethe methyl or ethyl ester, m y be empl ye or carbon atoms to make up thetotal of 13 or 14 the 926371 halide. Such as e acyl idecarbon atoms maybe in one or more side chains The resulting yl amino derivative is thenattached to the long chain at any of the positions condensed with theaid of a suitable mild dehyin the chain. Furthermore, in the unsaturatedso dratihg agent. s as P red calcium oxide. hydrocarbon radicals, theunsaturated condition to form t -alk 24a1kenyl) iml azolineasrepresented by one or more double bonds may The derivative thus preparedis then dehydrobe at any of th position in t hai h genated with the aidof a suitable dehydrogenaamples which follow will serve to illustratesome tion catalyst, h as nickel, to for e 2- of the various positions.Other branched chain alkyl 1 1) lmidazoleisomers having from 13 to 14carbon atoms with 35 The following es illustrate the pr cess at least 10carbon atoms in a long chain, when of e se i e tio an t ew co poundssubstituted in the 2-position of imidazole, a represulting therefrom.These examples are to be resented by the formula hereinbefore provided,construed as merely illustrative and not as limit are contemplated awithin t scope of t presing the scope of the present invention.

ent invention. The water-soluble salts of these EXAMPLE I compounds maybe prepared and are also valuable therapeutic agents. For example, thehyz'n'mdeclll'imidazole drochlorides, hydrobromides, acetates and other(iii-11H salts may be employed.

The new products and their water-soluble salts 0H2 (CHM CH3 may beadministered orally or parenterally and N have been found to beunusually effective in the A mixture of 426 gra s 1- m les) of nytreatment of various diseases. The acid salts ma myristate and 270 grams(4.5 moles) of anhybe prepared by dissolving the products in an drousethylene diamine was refluxed at C. aqueous solution containing thestoichiometrical for 10 hours. The excess ethylene diamine andequivalent of a suitable acid such as hydrochloric, the butanolresulting from the acylation were hydrobromic and acetic acids and thesolution then distilled oil, the distillation being completed may beemployed for parenteral administration. at a reduced pressure of 10 mm.The crude prod- Also the acid salts may be prepared during the M uctremaining in the still weighed 377 grams and syntheses of the imidazolederivatives or immemelted at about 122 C. with extensive previoussoftening. After recrystallization from alcohol. the melting point was150-152 C. The product was identified as N-n-tetradecanoyl ethylenediamine; the product was found to be appreciably soluble in benzene.

A mixture of 270 grams (imole) of the crude product described in theforegoing paragraph. and 280 grams (5 moles) of powdered calcium oxidewas heated with agitation at 225-230 C. for 36 hours. The mixture wasthen cooled and extracted with alcohol. The solvent was removed from theextract by evaporation, leavin 130 grams of crude amine base. The basewas distilled, yielding 70 grams of a pale yellow, crystalline, waxysolid material identified as 2-n-tridecyl imidazoline(2-n-tridecyl-4,5-dihydroimidazole); M. P., 87-88 C. with slightprevious softening. In place of distillation, the crude base may berecrystallized from benzene, alcohol, dioxane or a petroleum naphthasolvent. However, a pure product was difilcult to obtain in this manner.The small residue of uncondensed N-n-tetradecanoyl ethylene diaminewhich was extracted from the condensation reaction mixture by thealcohol together with the 2-n-tridecyl imidazoline was left in the stillafter distillation of the imidazoline.

In place of calcium oxide, other suitable dehydrating agents, such asother alkaline-earth oxides, for example, barium oxide and magnesiumoxide, and other mild dehydrating agents, may be employed. However,calcium oxide is the desired agent because of its cheapness andefficiency.

For the dehydrogenation of 2-n-tridecyl imidazoline, a nickel catalystwas prepared by heating n ckel formate in a mineral o il untildecomposition of the formate occurred. The nickel catalyst may beprepared by other methods, for example, the method disclosed in U. S.Patent No. 1,378,336, issued May 17, 192 1, to Ellis. Other suitabledehydrogenation catalysts, such as Raney nickel catalysts, may beemployed. One gram of the catalyst thus prepared was mixed with 18.9grams of 2-n-tridecyl imidazoline and the mixture was heated withagitation to 225- 235C. until hydrogen was no longer evolved.

The reaction mixture was cooled to 125 C. and gram of the nickelcatalyst was added. Heating was resumed and continued until theevolution of hydrogen ceased. The reaction mixture was then distilled invacuo; B. Pt. 230-235 C./'7 mm. The distilled product, upon cooling, wasa yellow solid and was identified as 2-n-tridecylimidazole; M. P. 80810.

EXAMPLE II 2 -n-tridecen-1 -yl-1 -imidazole CH--NH Two hundredninety-six (296) grams of freshly distilled myristic acid (1.6 moles)was melted and-poured into a one-literround-bottomed 3- necked flaskequipped with a mechanical stirrer, a reflux condenser (containing athermometer) and a dropping funnel. One hundred thirty-six (136) cc. ofbromine (2.66 moles) was added slowly to the acid, the rate of additionbeing adjusted so that the temperature remained at approximately 60 C.After the addition of bromine, the mixture was heated to approximately50-60 C. and maintained at that temperature for two hours. The reactionmixture was then allowed to stand overnight. The flask containing thereaction mixture was placed in an icesalt bath. To this mixture wasadded, with agitation, 250 cc. of water. The temperature rose rapidly toapproximately C. and the excess bromine was evolved. After the reactionhad subsided, the mixture .was heated at approximately 60 C. for abouttwo hours. The aqueous layer was removed by decantation and the residuallayer was washed with 250 cc. of water. The washed residue was heatedfor two hours at a temperature of approximately 50-70 C. and thereafterwas cooled and dissolved in 300 cc. of

, ether.- The ether'solution was washed five times with cc. portions ofwater. The washed ether solution was dried overnight over anhydrouscalcium chloride. The anhydrous ether solution was heated on the steambath to remove the ether. A yield of 328.1 grams of a-bromomyristic acid(82% based on myristic acid) was obtained.

A mixture or 61 grams (.198 mole) of a-bromomyristic acid and 51.6 grams(.4 mole) of quinoline was heated at 200 C. for five hours in a 600 cc.3-necked flask with stirring. To the reaction mixture 40 grams of 50%caustic soda solution was added, thereby causing the qulnoline toseparate'out. The quinoline was extracted from the reaction mixture with200 cc. benzene; a second extraction of the reaction mixture wasperformed with 200 cc. of ether, The residue was then washed with water.An aqueous solution of 50 cc. of concentrated hydrochloric acid in 50cc. of water was added to the residue. The mixture was then extractedwith 100 cc. of chloroform, using 25 cc. portions for the extractions.The chloroform layer was separated from the mixture and distilled toremove the hydrochloric acid. The resulting residue was identified asZ-tetradecenoic acid. The yield was 26.6 grams (59.4% based ona-bromo-myristic acid). The melting point of the crude acid was found tobe 504i3 C. (uncorrected) This acid, z-tetradecenoic acid, having theformula is a new compound. Its alkyl esters, salts and halidederivatives are also new compounds.

In place of quinoline, other suitable amines, such as dimethyl anilineor any of the quinaldines, may be employed.

An alkyl ester, such as the methyl or ethyl ester, of 2-tetradecenoicacid, was prepared and reacted by the method of Example I with amolecular equivalent of ethylene diamine to form N-n-tetradecen-2-oylethylene diamine having the formula The imidazoline derivative and thecorresponding imidazole derivative may be prepared from theN-acyl-ethylene diamine by the method of Ex ample I.

Examru: III

2- (1 ',1 -dimethyl-doclecyZ-1) -imidazole This derivative may beprepared according to the method of Example I, using an alkyl ester ofe,a-dimethyl-tridecanoic acid, such as the methyl or ethyl ester, inplace of the n-butyl ester of myristic acid.

Erma: IV 2- a-mfllfll-mn-l 1 41-1) 41731162010 CH-NH I! E (CHQeCH=OHaThis derivative may be prepared according to the method 0! Example I.using an alkyl ester, such as the methyl or ethyl ester, of z-methyl-IZ-tridecenoic acid in place 01' n-butyl myrlstate.

,I'his derivative may be prepared according to the method of Example I,using an ,alkyl ester, such as the methyl or ethyl ester, ofld-pentadecenoic acid in place or n-butyl myrlstate.

Examavl zn-tetmdecyl-imidazole OH-NH an c-omom)aon.

Thisderivativemaybeprcparedaccordinztothemethodoflxamplelusinganalkylester, suchasthemethylorthyleetenotn-pentadecanoic acid in place or n-butyl myristate.

Exams VII Z-tcflddecen-iZ-yl-i imidmle OH-NE This derivative may beprepared according to themethodoi'lxamplelusineenalkyleeter, such as themethyl or ethyl ester, of 13-hpentadecenoic acidin place of n-butylmyristate.

Exams VIII Z-a-tridecen-l-fl-f-finidasole cur-m:

aeeaeor asoie derivative may occur in positions other than thoseillustrated in the foregoing examples.

As illustrative of the therapeutic utility of the compounds of thepresent invention, the following data on the results obtained with2-n-tridecyl imidazole in tests conducted on two-week old duckllngsinoculated with large numbers of malaria germs, P. lophurae, are givenas follows:

n-Trid 1- n'Tiidml' 1mm Untreated mudm ig-z fig 13mins controls Dose .1:100 100 25 No. 0 i sngm. 5 5 6 5 Angmflerial activ- None (All drugs wereadministered twice daily lot 5 days.)

In addition to the aforedescribed therapeutic application, othertherapeutic applications of the derivatives of the present inventionhave been made with desirable results in instances in which with analkyl ester of a monocarboxylie acid in results were not predictable.

We claim: 1. The 2-tridecyl-imldazole of the formula:

(EH-NH Elf --CHa-(OHs)u' HI prepared for use as a therapeutic agent.

2. The z-tetradecyl-imidazole o! the formula:

prepared for use as a therapeutic aunt.

a. mason derivatives of the sol-mm; m

OENH

in which R represents a straight-chain alkylhydrocarhonradicalhavingfrom late carbon atoms. and acid salts thereof,prepared for use as therapeutic asents.

4. Aproceeeforpreparingtherapeuticasentaof the formula type.

on-mz in which It represents a straight-chain altyl hydrocarbon radicalhavins from 13 to 14 carbon atoms, comprisinng reacting ethylene dlaminewhich a carboxyl group is attached to a straightchain alkyl hydrocarbonradical having from 18 to 14 carbon stoma-recovering the N-acyl ethylenediamine derivative thus formed. heatinx said derivative in the presenceof a mild dehy- Gratin: scent, recovering the reaction product.

\ heating said reaction product with a'dehydrosedation catalyst andrecover-ins the dehydrodistiilation.

aenation product by LUCAS P. mines.

momma 8. MY.

